The present invention is based, in part, upon the discovery that a method of administration of N-acetylcysteine (NAC) markedly affects its effective biodistribution. The present invention provides a method for treating or mitigating the side effects, including organ damage, of cytotoxic cancer therapy for tumors located in the head or neck. Additionally, NAC or other thiols can be administered concurrently with, before or after, intra-arterial procedures and provides protective affects to prevent or diminish organ damage.
N-acetylcysteine (NAC) is an analog of cysteine. When NAC is administered to a mammal it is deacylated and enters a cellular synthetic pathway for the production of glutathione. Glutathione is involved in the cellular pathways influencing a tumor's resistivity to cytotoxic drugs. The cytotoxic properties of chemotherapeutic drugs can be enhanced by pretreatment with buthionine sulfoximine (BSO) thereby reducing intracellular glutathione. However, reduction of intracellular gluthionine will potentiate systemic toxicities associated with chemotherapeutic drugs. Thus, this procedure is dose-limiting. For protection, the glutathione levels of “normal” cells have to be reestablished if BSO is used to potentiate the cytotoxic properties of cytotoxic cancer therapies (Kamer et al., Cancer Res. 47:1593–1597, 1987; Ozols et al., Biochem. Pharm. 36:147–153, 1987; McLellan et al., Carcinogenesis 17:2099–2106, 1995; and Shattuck et al., J. Parenteral Enteral Nutrition 24:228–233, 1998). It may be possible to reduce the bone marrow toxicity of chemotherapeutic drugs by using sulfur-containing chemoprotective agents (thio, thiol, and thioether compounds) to mimic one or many of the activities of glutathione such as conjugation, free radical scavenging, and drug efflux via the multidrug resistance associated proteins. NAC and other thiol agents such as STS have early detoxifying activity not related to the later increase in glutathione levels. These early detoxifying effects occur because the thiols themselves mimic some actions of glutathione such as free radical scavenging, anti-oxidant activity, chemical conjugation, and activation of efflux pumps.
A potential problem with any chemoprotectant is the possibility of deactivating the anti-tumor effect of the chemotherapy or radiation therapy. The goal of chemoprotection is to reduce unwanted toxicities of chemotherapy or radiotherapy without affecting efficacy.
For brain tumor chemotherapy, one must attempt to increase the delivery of chemotherapy to the brain tumor and block the delivery of the chemoprotective agent. Additionally, one will want to target the chemoprotectant agent to the bone marrow to protect against myelosuppression and to liver, kidney and lung to prevent organ toxicity. Therefore, there is a need in the art to improve pharmacokinetics and biodistribution of chemoprotectant agents so that they will be more effective when delivered in a tissue-specific manner. Preferably, delivery is maximized to the bone marrow, chest and abdomen organs while minimized to the brain.
There are more than 10 specific active transport systems that transport compounds from the blood to the brain. Otherwise, substances, such as chemoprotectants can only nominally penetrate this barrier by passive diffusion. Brain tumors are particularly difficult to treat because the blood-brain barrier is an anatomical structure that limits the egress of constituents in the blood to the brain. Thus, brain tumors often respond poorly to chemotherapeutic drugs. There have been many attempts to try to increase brain bioavailability of various drug compounds to brain tissue. One technique uses osmotic BBB modification by administering mannitol through the internal carotid artery (Neuwelt et al., Cancer Res. 45:2827–2833, 1985). This technique is useful for administering the chemotherapeutic methotrexate to experimental brain tumors that would otherwise be inaccessible to this drug (it poorly crosses the BBB). The osmotic shrinkage caused by intracarotid mannitol administration allowed for temporary BBB disruption and increased tumor delivery of the methotrexate. Thus, a temporary disruption of the barrier functions of the BBB can be induced by a sugar, such as mannitol, and cause higher brain concentrations of a drug compound that would not otherwise have crossed the BBB. This BBB opening technique has also been investigated with other chemotherapeutic drugs (Neuwelt et al., Proc. Natl. Acad. Sci. USA 79:4420–4423, 1982; Fortin D. McCormich C I, Remsen L G, Nixon R, Neuwelt E A, “Unexpected neurotoxicity of etoposide phosphate when given in combination with other chemotherapeutic agents after blood-brain barrier modification using propofol for general anesthesia in a rat model,” Neurosurgery 47:199–207, 2000).
An example of chemoprotection is a drug neutralization technique described in U.S. Pat. No. 5,124,146 wherein excess toxic drug compounds are “mopped up” or bound by a binding or neutralizing agent not able to penetrate the blood brain barrier. This technique requires precise timing as to when the drug neutralizing agent is administered.
There are several thiol-based chemoprotectant agents that contain a thio, thiol, aminothiol or thioester moiety. Several thiol-based chemoprotectant agents have been shown to provide protection against at least some of the systemic toxicities caused by alkylating chemotherapeutics. The thiol based chemoprotective agents include N-acetyl cysteine (NAC), sodium thiosulfate (STS), GSH ethyl ester, D-methionine, and thiol amifostine (Ethyol or WR2721). NAC is currently marketed in the United States under an orphan indication for oral and intravenous (i.v.) administration for overdosing with acetaminophen. NAC has also been shown to be a chemoprotectant when administered in combination with a vanadate compound (U.S. Pat. No. 5,843,481; and Yarbo (ed) Semin. Oncol. 10 [Suppl 1]56–61, 1983). Ethyol is also marketed in the United States under the generic name of Amifostine. GSH ethyl ester is an experimental thiol not yet marketed for clinical use, but is representative of the class of thiols that is converted directly to glutathione.
In addition, NAC has been shown to be a mucoregulatory drug used for the treatment of chronic bronchitis (Grassi and Morandini, Eur. J. Clin. Pharmacol. 9:393–396, 1976; Multicenter Study Group, Eur. J. Respir. Dis. 61: [Suppl.]93–108, 1980; and Borman et al., Eur. J. Respir. Dis. 64:405–415, 1983).
In plasma, NAC can be present in its intact, reduced forms as well as in various oxidized forms. It can be oxidized to a disulfide by reacting with other low molecular weight thiols, such as cysteine and glutathione. NAC can be oxidized by reacting the thiol groups of plasma proteins. When administered intravenously, the brain levels of NAC are <5%. Yet, NAC does cross the BBB if given by an intra-arterial route of administration. NAC is rapidly cleared from plasma via the liver and kidney. Moreover, NAC does not show neurotoxic properties.
There are bioanalytical methods for the determination of NAC in plasma, including Cotgreave and Moldeus, Biopharm. Drug Disp. 8:365–375, 1987; and Johansson and Westerlund, J. Chromatogr. 385:343–356, 1986 that also permit a determination of other forms of NAC. Moreover, cysteine and cystine have been identified as major metabolites of NAC. The excreted urinary product is inorganic sulfate together with small amounts of taurine and unchanged NAC. According to the label indications for NAC manufactured by (American Regent Laboratories Shirley, N.Y.), vials of NAC are produced as a sterile solution for oral administration diluted with water or soft drinks.
Another thiol-containing chemoprotectant is sodium thiosulfate (STS). Its chemical formula is Na2S2O3 and it has been used clinically for cyanide poisoning and for nephrotoxicitiy caused by cisplatin. STS is cleared rapidly from circulation primarily by the kidney. The plasma half life after a bolus injection is about 17 minutes. STS can also inactivate platinum agents through covalent binding to platinum agents at a molar excess >40:1 (STS:platinum). With i.v. administration of STS, the brain levels of STS are <5% of blood showing poor brain localization. Neurotoxic side effects, in the form of seizures, may occur when brain levels of STS are enhanced through i.a. administration within 30 min of BBB disruption.
Diagnostic or therapeutic procedures involving intra-arterial catheterization can cause a variety of organ toxicities, complications and side effects from injuries. For example, placement of an arterial catheter can dislodge plaques from artery walls that can lodge elsewhere in the vasculature causing ischemia. Ischemia increases the presence of free radicals and leads to cell death. As another example, nephrotoxicity of radiographic contrast agents can lead to acute renal failure even when measures are taken to reduce toxic effects. As a third example, intra-arterial catheterization is used during angioplasty procedures wherein a balloon catheter is inserted into the arterial circulation and then threaded (with radiographic contrast agents for visualization) to a site of occlusion. In dilating the occluded artery, various forms of tissue damage and inflammatory reactions (e.g., restenosis) can occur including ischemic tissue injury.
Specifically, toxic side effects of intra-arterial catheterization and infusion of radiographic contrast agents prolong hospital stays, add to the cost of medical care, and can be fatal. The incidence of radiographic-contrast-agent-induced acute renal failure, currently estimated to be as high as 50 percent among patients with diabetes mellitus and preexisting renal disease who receive contrast agents, is likely to remain high as the use of invasive intra-arterial procedures to diagnose and treat complex disease continues to grow.
Radiographic contrast agents are used in medical imaging. Medical imaging is the production of images of internal organs and tissues by the application of nonsurgical techniques. Contrast agents are chemicals used to enhance the image, and to increase contrast between the target organ and surrounding tissues. Prevention or mitigation of renal failure after the administration of a radiographic contrast agent has been notably difficult. Calcium-channel antagonists, adenosine antagonists, and dopamine have all been used without convincing evidence of benefit.
Tepel et al. proposed the oral administration of approximately 1200 mg of N-acetylcysteine per day, given orally in divided doses on the day before and on the day of the administration of the radiographic contrast agent. (Tepel et al., New England J. Med., Jul. 20, 2000). Oral administration allegedly prevented the expected decline in renal function in all patients with moderate renal insufficiency, and therefore high risk, who were undergoing computed tomography.
NAC has been used successfully to ameliorate the toxic effects of a variety of experimentally or clinically induced ischemia-reperfusion syndromes of the heart, kidney, lung, and liver. In each of these syndromes, it is thought that the activity of NAC is related to its action as a free-radical scavenger, or as a reactive sulphydryl compound that increases the reducing capacity of the cell. The specific mechanism of NAC to prevent the nephrotoxic effects of contrast agents is not known.
Therefore, there is a need in the art to find better ways to use thiol-based chemoprotectants, such as NAC and STS and to take advantage of their pharmacokinetic properties. There is also a need in the art to find better, higher dose cytotoxic treatment regimens for head and neck as well as brain tumors that avoid dose-limiting due to side effects.
There is a need in the art for a compound that can be used with intra-arterial catheterization procedures to reduce organ toxicity. Diabetic patients with markedly reduced renal function, in whom coronary angiography is often delayed because of the considerable risks to renal function entailed by angiography, may particularly be benefited by targeted delivery of a protectant agent. Additionally, there is a need in the art for a low cost compound which is generally available, easy to administer and has limited side effects. There is a need in the art for a compound and a method of administration of the compound that can be used to reduce or eliminate tissue damage caused by intra-arterial procedures.
Additionally, there is a need in the art to find better ways to use thiol-based radiographic protectants, such as NAC and STS (sodium thiosulfate) and to take advantage of their pharmacokinetic properties. There is also a need in the art to find an agent protective against intra-arterial catheterization-induced reductions in organ function. These and other problems of the prior art are solved by the present method and pharmaceutical composition.